Treatment of cns conditions

ABSTRACT

Aspects of the present invention relate to a method of treating an epileptic encephalopathy in a mammal in need thereof, comprising administering a composition comprising an effective amount of (4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof to the mammal.

TECHNICAL FIELD

The present invention relates to a method of treating an epilepticencephalopathy in a mammal in need thereof, comprising administering acomposition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof to the mammal.

BACKGROUND OF THE INVENTION

The term epileptic encephalopathies describes a heterogeneous group ofepilepsy syndromes in which the epileptic activity itself may contributeto severe cognitive and behavioral impairments above and beyond whatmight be expected from the underlying pathology alone (e.g., corticalmalformation) and that can worsen over time. These disorders aregenerally diagnosed in childhood and adolescence, varying in theiretiologies, seizure types, electroencephalographic patterns, cognitivedeficits, and prognosis, while sharing a consistent and significantimpact on neurological development.

Patent document 1 describes the compound,(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone,having a superior CH24H inhibitory action shown below as Formula (I):

DOCUMENT LIST Patent Document

-   [Patent Document 1] U.S. Pat. No. 8,648,079

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a superior method oftreating an epileptic encephalopathy in a mammal in need thereof,comprising administering a composition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof to the mammal.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problem and found that a novel method oftreating an epileptic encephalopathy in a mammal in need thereof,comprising administering a composition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof to the mammal, which resultedin the completion of the present invention.

Accordingly, the present invention provides the following:

[1] A method of treating an epileptic encephalopathy in a mammal in needthereof, comprising administering a composition comprising an effectiveamount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof to the mammal.[2] The method of the above-mentioned [1], wherein the epilepticencephalopathy is selected from the group of Dravet syndrome (DS), Earlymyoclonic encephalopathy, Epilepsy with continuous spike-and-wavesduring slow-wave sleep (other than Landau-Kleffner syndrome), epilepsyof infancy with migrating focal seizures, Hypothalamic epilepsy,Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), Doose syndrome(myoclonic-astatic epilepsy), Myoclonic status in non-progressiveencephalopathies, Ohtahara syndrome or early infantile epilepticencephalopathy, West syndrome, Glycine encephalopathy, 15q duplicationsyndrome (Dup 15q) and Tuberous Sclerosis Complex (TSC) and seizuresassociated with mutations in CHD2, Cyclin-Dependent Kinase-Like 5(CDKL5), SCN1A, SCN2A, SCN8A, ARK, KCNA1, KCNA2, KCNT1, KCNQ2, HCN1,PCDH19, GRIN1, GRIN2A and GRIN2B.[3] The method of the above-mentioned [1], wherein the epilepticencephalopathy is selected from the group of Dravet syndrome (DS),Lennox-Gastaut syndrome (LGS), Tuberous Sclerosis Complex (TSC) andseizures associated with mutations in CHD2, Cyclin-Dependent Kinase-Like5 (CDKL5), SCN1A, SCN2A, SCN8A, ARK, KCNA1, KCNA2, KCNT1, KCNQ2, HCN1,PCDH19, GRIN1, GRIN2A and GRIN2B.[4] The method of any of the above-mentioned [1] to [3], whereinadministering the effective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof results in (i) a reduction in the frequency of seizures in themammal and/or (ii) a reduction in the plasma 24HC levels in the mammal.[5] The method of any of the above-mentioned [1] to [4], wherein theeffective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof is administered orally.[6] The method of any of the above-mentioned [1] to [5], wherein theeffective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof is administered as a single unit dose.[7] The method of the above-mentioned [6], wherein the single unit doseis at least about 0.8 mg/kg.[8] The method of the above-mentioned [6] or [7], wherein the singleunit dose is between about 2 mg/kg and about 12 mg/kg.[9] The method of any of the above-mentioned [6] to [8], wherein thesingle unit dose is selected from the consisting of about 0.8 mg/kg,about 2 mg/kg, about 3 mg/kg, about 3.33 mg/kg, about 4 mg/kg, about 5mg/kg, about 6 mg/kg, about 10 mg/kg, and about 12 mg/kg.[10] The method of any of the above-mentioned [1] to [9], wherein theeffective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof is administered according to a dose regimen of either twice aday (BID) or once a day (QD) dosing.[11] The method of any of the above-mentioned [1] to [10], wherein themammal is a human.[12] The method of the above-mentioned [11], wherein the human is anadult (18 years old or older), a juvenile (between 12 and 17 years old,endpoint inclusive), a child (between 2 and 11 years old, endpointinclusive), an infant (between 1 month and 1 year of age, endpointinclusive).[13] The method of the above-mentioned [11] or [12], wherein theeffective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof is administered as a single unit dose.[14] The method of the above-mentioned [13], wherein the single unitdose is less than about 1350 mg.[15] The method of the above-mentioned [13] or [14], wherein the singleunit dose is between about 50 mg and about 800 mg.[16] The method of any of the above-mentioned [13] to [15], wherein thesingle unit dose is between about 100 mg and about 800 mg.[17] The method of any of the above-mentioned [13] to [16], wherein thesingle unit dose is selected from the group consisting of about 100 mg,about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg andabout 800 mg.[18] The method of the above-mentioned [11], wherein the effectiveamount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof is administered twice a day.[19] The method of the above-mentioned [18], wherein(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone isadministered at the daily dose of between about 100 mg and about 800 mg.[20] The method of the above-mentioned [18] or [19], wherein(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone isadministered according to a dose regimen selected from the groupconsisting of about 50 mg twice a day, about 100 mg twice a day, about200 mg twice a day, about 300 mg twice a day and about 400 mg twice aday.[21] The method of any of the above-mentioned [18] to [20], wherein(4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone isadministered according to a dose regimen of about 400 mg twice a day.[22] The method of any of the above-mentioned [1] to [21], furthercomprising administering an additional composition comprising aneffective amount of an additional anti-epileptic drug.[23] The method of the above-mentioned [22], wherein the additionalanti-epileptic drug is selected from the group of acetazolamide,brivaracetam, bromide, cannabidiol, carbamazepine, clobazam, clonazepam,diazepam, eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoinsodium, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam,mephenytoin, methlyphenobarbital, methosuximide, nitrazepam,oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin,pregabalin, primidone, retigabine, rufinamide, sodium valproate,stiripentol, tiagabine, topiramate, fenfluramine, vigabatrin, andzonisamide.[24] The method of any of the above-mentioned [1] to [21], wherein thecomposition further comprises one or more of an additionalanti-epileptic drug and a pharmaceutically acceptable carrier.[25] The method of the above-mentioned [24], wherein the additionalanti-epileptic drug is selected from the group of acetazolamide,brivaracetam, bromide, cannabidiol, carbamazepine, clobazam, clonazepam,diazepam, eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoinsodium, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam,mephenytoin, methlyphenobarbital, methosuximide, nitrazepam,oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin,pregabalin, primidone, retigabine, rufinamide, sodium valproate,stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.[26] A pharmaceutical composition comprising(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof, which is for treating anepileptic encephalopathy.[27] (4-Benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanoneor a pharmaceutically acceptable salt thereof for use in treatment ofepileptic encephalopathy.

Effect of the Invention

A pharmaceutical composition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is useful for the prophylaxisor treatment of epileptic encephalopathy. According to the presentinvention, a superior method of treating an epileptic encephalopathy ina mammal in need thereof, comprising administering a compositioncomprising an effective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof to the mammal can be provided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail in the following.

Aspects of the present invention relate to a method of treating anepileptic encephalopathy in a mammal in need thereof, comprisingadministering a composition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof to the mammal.

In some embodiments, the epileptic encephalopathy is selected from thegroup of Dravet syndrome (DS, severe myoclonic epilepsy in infancy),Early myoclonic encephalopathy, Epilepsy with continuous spike-and-wavesduring slow-wave sleep (other than Landau-Kleffner syndrome), epilepsyof infancy with migrating focal seizures, Hypothalamic (gelastic)epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), Doosesyndrome (myoclonic-astatic epilepsy), Myoclonic status innon-progressive encephalopathies, Ohtahara syndrome or early infantileepileptic encephalopathy, West syndrome, Glycine encephalopathy, 15qduplication syndrome (Dup15q) and Tuberous Sclerosis Complex (TSC) andseizures associated with mutations in CHD2, Cyclin-Dependent Kinase-Like5 (CDKL5), SCN1A, SCN2A, SCN8A, ARX, KCNA1, KCNA2, KCNT1, KCNQ2, HCN1,PCDH19, GRIN1, GRIN2A, GRIN2B, GRIN2D, CACNA1A, GABABRA1, GABRB1,GABRB2, GABRB3, GABRG2, ATP1A2, SLC2A1, SLC6A1, STXBP1 and SYNGAP1.

In some embodiments, the epileptic encephalopathy is selected from thegroup of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), andTuberous Sclerosis Complex (TSC).

In some embodiments, administering the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof results in (i) a reduction inthe frequency of seizures in the mammal and/or (ii) a reduction in theplasma 24HC levels in the mammal.

In some embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered orally.

In some embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered as a singleunit dose, optionally of at least about 0.8 mg/kg, between about 2 mg/kgand about 12 mg/kg, about 2 mg/kg, about 3 mg/kg, about 3.33 mg/kg,about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, or about 12mg/kg.

In some embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered as a dailydose, between about 50 mg twice a day (BID), about 100 mg BID, about 200mg BID or about 300 mg BID.

In some embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered according to adose regimen of either twice a day (BID) or once a day (QD) dosing.

In some embodiments, the mammal is a human, optionally, an adult (18years old or older), a juvenile (between 12 and 17 years old, endpointinclusive), a child (between 2 and 11 years old, endpoint inclusive), aninfant (between 1 month and 1 year of age, endpoint inclusive). Infurther embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered as a singleunit dose, optionally of less than about 1350 mg, between about 50 mgand about 800 mg, (preferably between about 100 mg and about 800 mg),about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg,about 400 mg, about 600 mg or about 800 mg.

In some embodiments, the mammal is a human, optionally, an adult (18years old or older), a juvenile (between 12 and 17 years old, endpointinclusive), a child (between 2 and 11 years old, endpoint inclusive), oran infant (between 1 month and 1 year of age, endpoint inclusive). Infurther embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered twice a day,optionally of about 50 mg BID, 100 mg BID, 200 mg BID, 300 mg BID, or400 mg BID (preferably 300 mg BID or 400 mg BID).

In some embodiments, the method further comprises administering anadditional composition comprising an effective amount of an additionalanti-epileptic drug, optionally acetazolamide, brivaracetam, bromide,cannabidiol, carbamazepine, clobazam, clonazepam, diazepam,eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoin sodium,gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam,mephenytoin, methlyphenobarbital, methosuximide, nitrazepam,oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin,pregabalin, primidone, retigabine, rufinamide, sodium valproate,stiripentol, tiagabine, topiramate, vigabatrin, zonisamide, everolimus,allopregnalone, Cenobamate, Fenfluramine hydrochloride, Ganaxolone,Immunoglobulin (human), ADX-71149, alprazolam, ataluren, buspironehydrochloride, cannabidivarin, DP-VPA, naluzotan hydrochloride,PF-06372865, BM-MSCs (autologous), CPP-115, E-2730, huperzine A,radiprodil, SAGE-217, SAGE-516, [11C]UCB-J, AN2/AVex-73, AVL-5189, Alpha1-24 corticotropin, CUR-1916, LY-3130481, MP-101, Metforminhydrochloride, SAGE-689, SF-0034 or TRP-005.

In some embodiments, the composition further comprises one or more of anadditional anti-epileptic drug, optionally acetazolamide, brivaracetam,bromide, cannabidiol, carbamazepine, clobazam, clonazepam, diazepam,eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoin sodium,gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam,mephenytoin, methlyphenobarbital, methosuximide, nitrazepam,oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin,pregabalin, primidone, retigabine, rufinamide, sodium valproate,stiripentol, tiagabine, topiramate, vigabatrin, or zonisamide, and apharmaceutically acceptable carrier, optionally an excipient, lubricant,binder, disintegrant, solvent, solubilizing agent, suspending agent,isotonicity agent, buffer, soothing agent, preservative, antioxidant,colorant, and sweetening agent.

Aberrant cholesterol metabolism is implicated in epilepsydisorders/syndromes. In the brain, cholesterol is metabolized bycholesterol 24-hydroxylase (CH24H), which is specifically andconstitutively expressed in neurons, to 24S-hydroxycholesterol (24HC).24HC leaves the brain via lipoproteins and is excreted in bile.

Under normal conditions, extracellular glutamate is sequestered byglutamate transporters on neighboring astrocytes which require adequatecholesterol levels to efficiently maintain lipid raft structures in theastrocyte plasma membrane. Upon central nervous system (CNS) injury,CH24H is induced in reactive astrocytes and microglia. This leads todisruption in astrocytic glutamate homeostasis and a large increase inextracellular glutamate levels. As the CH24H enzyme converts cholesterolessential for the integrity of plasma membrane lipid rafts to 24HC, thecirculating levels of 24HC increase, and may further contribute tounderlying pathophysiological processes. Excessive extracellularglutamate and 24HC levels are thought to play major roles inexcitotoxicity either through a sustained activation of theN-methyl-D-aspartate (NMDA) receptor channel or as a positive allostericmodulator of the receptor. The processes may be equally important incontributing to the enhanced glutamatergic activity observed in epilepsydisorders. Neurochemical processes, such as differential expression ofgenes and/or changes in neuroplasticity, occur in children at adifferent rate than in adults. This rate of change may represent anadditional and nonspecific risk in children who are geneticallypredisposed to seizures. For example, the levels of 24HC can be up to 3times higher in small children when compared to adults; it is,therefore, possible that the increased levels of 24HC in the children'sbrain are linked to more severe convulsions observed in rare epilepticsyndromes. The compound (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone, shown below as Formula (I) is describedin U.S. Pat. No. 8,648,079:

The compound of Formula (I) is a CH24H inhibitor. Aspects of thisdisclosure relate to a method of treating an epileptic encephalopathy ina mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat;preferably human) in need thereof, comprising administering acomposition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof to the mammal.

In some embodiments, the epileptic encephalopathy is selected from thegroup of Dravet syndrome (DS, severe myoclonic epilepsy in infancy),early myoclonic encephalopathy (Doose syndrome), Epilepsy withcontinuous spike-and-waves during slow-wave sleep (other thanLandau-Kleffner syndrome), epilepsy of infancy with migrating focalseizures, Hypothalamic (gelastic) epilepsy, Landau-Kleffner syndrome,Lennox-Gastaut syndrome (LGS), Doose syndrome (myoclonic-astaticepilepsy), Myoclonic status in non-progressive encephalopathies,Ohtahara syndrome or early infantile epileptic encephalopathy, Westsyndrome, Glycine encephalopathy, 15q duplication syndrome (Dup15q) andTuberous Sclerosis Complex (TSC) and seizures associated with mutationsin CHD2, Cyclin-Dependent Kinase-Like 5 (CDKL5), SCN1A, SCN2A, SCN8A,ARX, KCNA1, KCNA2, KCNT1, KCNQ2, HCN1, PCDH19, GRIN1, GRIN2A and GRIN2B.

In some embodiments, the epileptic encephalopathy also meansdevelopmental and epileptic encephalopathy.

In some embodiments, the epileptic encephalopathy is selected from thegroup of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), andTuberous Sclerosis Complex (TSC).

As used herein, the term “treating” includes the prevention, reduction,and/or complete resolution of the symptoms associated with or the causeof the target indication and/or a lessening of severity of thecondition.

As used herein, the term “effective amount” intends an amount effectiveto successfully achieve a particular biological effect. In the presentcase, the effective amount is an amount to effective to treat anepileptic encephalopathy. Suitable effective amounts may be determinedaccording to methods well known in the art to determine single unitdosage and/or dose regimens.

In some embodiments, the contents of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof in the present composition may vary from about 10% (w/w) toabout 100% (w/w). Thus, the present composition may be(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof themselves.

In some embodiments, administering the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof results in (i) a reduction inthe frequency of seizures in the mammal and/or (ii) a reduction in theplasma 24HC levels in the mammal.

In some embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered according to adose regimen of either twice a day (BID) or once a day (QD) dosing.

The term “single unit dose” in this context refers to an effectiveamount provided in a single administration. Non-limiting examples of asuitable single unit doses for use in the claimed methods include atleast about 0.8 mg/kg, between about 2 mg/kg and about 12 mg/kg, about 2mg/kg, about 3 mg/kg, about 3.33 mg/kg, about 4 mg/kg, about 5 mg/kg,about 6 mg/kg, about 10 mg/kg, or about 12 mg/kg.

The term “dose regimen” in this context refers to an effective amountprovided over a fixed number of administrations over a specifiedduration of time.

In some embodiments, the mammal is a human, optionally, an adult (18years old or older), a juvenile (between 12 and 17 years old, endpointinclusive), a child (between 2 and 11 years old, endpoint inclusive), aninfant (between 1 month and 1 year of age, endpoint inclusive). It isappreciated that single unit doses may be tailored to the mammal beingtreated. For example, for humans, non-limiting exemplary single unitdoses include less than about 1350 mg, between about 50 mg and about 800mg (preferably between about 100 mg and about 800 mg), about 100 mg,about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg orabout 800 mg.

Suitable routes of administration and doses and formulations suitedthereto are known in the art. Non-limiting examples of routes ofadministration relevant to the claimed methods include oral andparenteral (e.g., topical, rectal, or intravenous) routes. Examples ofthe dosage form suited for a particular route of administration includeoral preparations such as tablet (including sugar-coated tablet,film-coated tablet, sublingual tablet, orally disintegrating tablet),capsules (including soft capsule, microcapsule), granule, powder,troche, syrup, emulsion, suspension, films (e.g., orally disintegrablefilms) and the like; and parenteral agents such as injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection, drip infusion), external preparations (e.g.,dermal preparation, ointment), suppository (e.g., rectal suppository,vaginal suppository), pellet, nasal preparation, pulmonary preparation(inhalant), eye drop and the like. Optionally, these preparations may bea release control preparation (e.g., sustained-release microcapsule)such as an immediate-release preparation or a sustained-releasepreparation.

In some embodiments, the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered orally.

In some embodiments, the method further comprises administering anadditional composition comprising an effective amount of an additionalanti-epileptic drug. In other embodiments, the composition comprisingthe effective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof further comprises one or more of an additional anti-epilepticdrug.

Non-limiting examples of additional anti-epileptic drugs includeacetazolamide, brivaracetam, bromide, cannabidiol, carbamazepine,clobazam, clonazepam, diazepam, eslicarbazepine acetate, ethosuximide,felbamate, fosphenytoin sodium, gabapentin, lacosamide, lamotrigine,levetiracetam, lorazepam, mephenytoin, methlyphenobarbital,methosuximide, nitrazepam, oxcarbazepine, perampanel, piracetam,phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide,sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, andzonisamide.

In some embodiments, the composition comprising the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof further comprises apharmaceutically acceptable carrier.

As used herein, the term “pharmaceutically acceptable carrier” intendsone or more organic or inorganic carrier substances conventionally usedin the formulation of pharmaceutical compositions.

Suitable pharmaceutically acceptable carriers can be determined bymethods well known in the art, e.g. excipients, lubricants, binders anddisintegrants; solvents, solubilizing agents, suspending agents,isotonicity agents, buffers, and soothing agents; and/or preparationadditives such as preservatives, antioxidants, colorants, and sweeteningagents.

In some embodiments, the pharmaceutically acceptable carrier is anexcipient, lubricant, binder, disintegrant, solvent, solubilizing agent,suspending agent, isotonicity agent, buffer, soothing agent,preservative, antioxidant, colorant, and sweetening agent.

Non-limiting examples of such suitable pharmaceutically acceptablecarriers include:

for an excipient: lactose, sucrose, D-mannitol, D-sorbitol, starch,gelatinated starch, dextrin, crystalline cellulose, low-substitutedhydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic,pullulan, light anhydrous silicic acid, synthesis aluminum silicate andmagnesium alumino metasilicate;

for a lubricant: magnesium stearate, calcium stearate, talc andcolloidal silica;

for a binder: gelatinated starch, sucrose, gelatin, gum arabic,methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin,pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose andpolyvinylpyrrolidone;

for a disintegrant: lactose, sucrose, starch, carboxymethylcellulose,calcium carboxymethylcellulose, croscarmellose sodium, sodiumcarboxymethyl starch, light anhydrous silicic acid and low-substitutedhydroxypropylcellulose;

for a solvent: water, physiological brine, Ringer's solution, alcohol,propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oiland cottonseed oil;

for a solubilizing agent: polyethylene glycol, propylene glycol,D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodiumsalicylate and sodium acetate;

for a suspending agent: surfactants such as stearyltriethanolamine,sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkoniumchloride, benzethonium chloride, and glycerol monostearate; hydrophilicpolymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodiumcarboxymethylcellulose, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and the like;polysorbates, and polyoxyethylene hydrogenated castor oil;

for an isotonicity agent: sodium chloride, glycerol, D-mannitol,D-sorbitol and glucose;

for a buffer: phosphate, acetate, carbonate, and citrate;

for a soothing agent: benzyl alcohol;

for a preservative: p-oxybenzoates, chlorobutanol, benzyl alcohol,phenethyl alcohol, dehydroacetic acid, and sorbic acid;

for an antioxidant: sulfite and ascorbate;

for a colorant: aqueous water-soluble food tar colors (e.g., food colorssuch as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5,Food Color Blue Nos. 1 and 2 and the like), water insoluble lake dyes(e.g., aluminum salt of the above-mentioned water-soluble food tarcolor), and natural dyes (e.g., β-carotene, chlorophyll, ferric oxidered); and

for a sweetening agent: saccharin sodium, dipotassium glycyrrhizinate,aspartame, and stevia.

Examples of a metabolite of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone include a compound shown below:

The invention is further illustrated by, though in no way limited to,the following examples.

EXAMPLES Example 1—Safety and Efficacy Studies

Four clinical studies including a single-rising dose (SRD)first-in-human study, a single-dose positron emission tomography (PET)target occupancy study, a multiple-rising dose (MRD) study, and asingle-dose relative bioavailability (BA) and food-effect study wereconducted.

The pharmacokinetics (PK) and pharmacodynamics (PD) of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone werecharacterized in these studies.

The results of the PET study provided clinical evidence ofdose-dependent decreases in plasma 24HC concentrations and PET occupancymeasurements that were dose- and time-dependent and correlated withcirculating levels of 24HC. Tables 1-1 and 1-2 show the results ofsafety evaluation.

TABLE 1-1 Reporting Groups (Time Frame 30 Days) Placebo-matchingsolution, Cohorts 1-6: Placebo orally, once, on Day 1. Cohort 1: 15 mgof (4- (4-benzyl-4- benzyl-4-hydroxypiperidin-1-hydroxypiperidin-1-yl)(2,4′- yl)(2,4′-bipyridin-3-bipyridin-3-yl)methanone 15 yl)methanone mg solution, orally, once, onDay 1. Cohort 2: 50 mg of (4- (4-benzyl-4- benzyl-4-hydroxypiperidin-1-hydroxypiperidin-1-yl)(2,4′- yl)(2,4′-bipyridin-3-bipyridin-3-yl)methanone 50 yl)methanone mg solution, orally, once, onDay 1. Cohort 3: 200 mg of (4- (4-benzyl-4- benzyl-4-hydroxypiperidin-1-hydroxypiperidin-1-yl)(2,4′- yl)(2,4′-bipyridin-3-bipyridin-3-yl)methanone 200 yl)methanone mg solution, orally, once, onDay 1. Cohort 4: 600 mg of (4- (4-benzyl-4- benzyl-4-hydroxypiperidin-1-hydroxypiperidin-1-yl)(2,4′- yl)(2,4′-bipyridin-3-bipyridin-3-yl)methanone 600 yl)methanone mg solution, orally, once, onDay 1. Cohort 5: 900 mg of (4- (4-benzyl-4- benzyl-4-hydroxypiperidin-1-hydroxypiperidin-1-yl)(2,4′- yl)(2,4′-bipyridin-3-bipyridin-3-yl)methanone 900 yl)methanone mg solution, orally, once, onDay 1. Cohort 6: 1350 mg of (4- (4-benzyl-4-benzyl-4-hydroxypiperidin-1- hydroxypiperidin-1-yl)(2,4′-yl)(2,4′-bipyridin-3- bipyridin-3-yl)methanone 1350 yl)methanone mgsolution, orally, once, on Day 1.

TABLE 1-2 Serious Adverse Events Total, Serious Adverse Events #participants affected/at risk Cohorts 1-6: Placebo 0/12 (0.00%)  Cohort1: 15 mg 0/6 (0.00%) Cohort 2: 50 mg 0/6 (0.00%) Cohort 3: 200 mg 0/6(0.00%) Cohort 4: 600 mg 0/6 (0.00%) Cohort 5: 900 mg 0/6 (0.00%) Cohort6: 1350 mg 0/6 (0.00%)

No serious pretreatment events or post treatment adverse events werereported.

The safety results from these studies show that doses up to 1350 mgsingle dose is generally safe and well tolerated in healthy male andfemale subjects (Tables 1-1 and 1-2).

A further safety and tolerability study is being conducted to examinethe safety, tolerability, pharmacokinetics (PK), and pharmacodynamics(PD) of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone as an adjunctive therapy in humansubjects with epileptic encephalopathies.

The study examines adult subjects between the ages of 18 and 65 withepileptic encephalopathies, including but not limited to Dravet Syndrome(DS), Lennox-Gastaut Syndrome (LGS), and Tuberous Sclerosis Complex(TSC), demonstrating countable motor seizures (i.e., 2 per month duringthe past 3 months).

The study enrolls 20 subjects. The study examines the safety andtolerability of 100 mg, 200 mg and 300 mg BID doses vs. placebo inpatients with epileptic encephalopathies. Efficacy (seizure count usinga daily seizure diary completed by the patients or their care giver), PKand 24HC levels are also collected in the study.

At the Screening Visit, informed consent and/or assent (if applicable)is obtained from the subjects and/or subjects' legally acceptablerepresentative. Subjects undergo screening procedures to assess studyeligibility in accordance with the study entry criteria. At thisScreening Visit and at subsequent visits, subjects and/or subjects'caregivers are provided with a seizure diary and are instructed torecord seizure data on a daily basis starting at Baseline and throughoutthe study. The seizure diary data collected during a 4-week period isused as the baseline seizure data for endpoint analysis. PD blood samplecollection for measurement of baseline plasma 24HC levels is also doneat the Screening Visit. The 4-week Baseline Period seizure diaryrecording can begin as soon as informed consent has been signed. At theend of the 4-week Baseline Period and after confirmation of eligibility,subjects return to the clinic on Day 1 in Part 1 for randomization. If asubject does not meet the eligibility criteria during theScreening/Baseline Period, the subject is discontinued from the study.

The study consists of 2 parts:

Part 1 is a randomized double-blind part consisting of 3 periods: ascreening/baseline period (4-6 weeks), titration period (20 days), andmaintenance period (10 days). The target final dose of 300 mg BID isreached after a 20-day titration period.

Part 2 is an open-label continuation part consisting of 4 periods: atitration period (10 days), maintenance period (44 days), de-escalationperiod (3-6 days) and follow-up period (30 days).

Part 1 of the study is designed to investigate the safety, tolerability,PK, and PD in adult subjects with developmental and/or epilepticencephalopathies in a double-blind manner. Efficacy of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone onseizure frequency is investigated in an exploratory manner. A total of20 adult subjects who demonstrate ≥1 bilateral motor seizure (dropseizures, tonic-clonic, tonic, bilateral clonic, atonic,myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateralhyperkinetic motor features) during the 4-week Baseline Period israndomly assigned on Day 1 to receive (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone (n=16) or matching placebo (n=4) twicedaily (BID) orally for 30 days during the Double-Blind Treatment Period.Subjects initiate IP (investigational product);(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone orplacebo) at 100 mg BID from Days 1 through 10. Subjects who cannottolerate the 100 mg BID dosing are withdrawn from the study. On Day 11,subjects return to the clinic and the IP dose is increased to 200 mgBID; this dose level is maintained from Days 11 through 20 but isreduced to 100 mg BID in subjects who cannot tolerate the 200 mg BIDdose or demonstrate safety concerns, based on the investigator'sjudgement and in consultation with the subject's caregiver, whenapplicable. On Day 21, subjects return to the clinic; at this visit, theinvestigator reviews the subject's safety data and discusses thebenefit-risk assessment with the subject or subject's legally acceptablerepresentative before proceeding to increase the dose from 200 mg BID to300 mg BID, and this dose level is maintained from Days 21 through 30.The dose may be reduced to 200 mg BID in subjects who cannot toleratethe 300 mg BID dose or demonstrate safety concerns, as described above.Subjects for whom the dose was reduced to a lower dose level stay onthat dose level until the end of the Double-Blind Treatment Period.

Three days after each dose up-titration or de-escalation, subjects arecontacted by phone to monitor study drug compliance, concomitantmedication use, and AEs. Any change in dose is documented in thesubject's clinic chart and the subject's caregiver is advised to notethe same in the dosing card.

On Day 1, PK, PD, anti-epileptic drug, and optional PGx blood sampleswill be collected before the morning dose of study drug. PK and PD bloodsamples are also collected at 1, 3, and 5 hours after the morning doseon Day 1. On Day 11 and Day 21, PK and PD blood samples (before andapproximately 1 hour after morning dose), an anti-epileptic drug bloodsample (before morning dose), and seizure diary data are collected.Subjects who are unwilling to continue into Part 2 of the study proceeddirectly to the Final Visit, including dose de-escalation, asappropriate, followed by the 30-day Follow-up Period.

Part 2 of the study is designed to investigate the safety, tolerability,PK, and PD of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone in adult subjects with—epilepticencephalopathies in an open-label manner. All subjects who complete theDouble-Blind Treatment Period in Part 1 have the option to continuedirectly into the Open-Label Treatment Period in Part 2. Because somesubjects may enter Part 2 after receiving placebo and others(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone up to300 mg BID and to maintain the study blind, all subjects start on(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone 200 mgBID at the start of Part 2. On Day 31, subjects return to the clinic andreceive (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone 200 mg BID from Days 31 to 40 but may bereduced to 100 mg BID in subjects who cannot tolerate the 200 mg BIDdose or demonstrate safety concerns, based on the investigator'sjudgement and in consultation with the subject's caregiver, whenapplicable. Subjects who cannot tolerate the 100 mg BID dose ordemonstrate safety concerns, based on the investigator's judgement andin consultation with the subject's caregiver, is discontinued from thestudy. On Day 41, subjects return to the clinic; at this visit, theinvestigator review the subject's safety data and discuss thebenefit-risk assessment with the subject or subject's legally acceptablerepresentative before proceeding to increase the dose from 200 mg BID to300 mg BID, and this dose level is maintained until the Final Visit forthe dose de-escalation phase. Subjects' dose may be increased ordecreased before Day 41 based on clinical condition (i.e., increasingseizures) and investigator judgment. This dose may be reduced to 200 mgBID in subjects who cannot tolerate the 300 mg BID dose or demonstratesafety concerns, as described above. Subjects for whom the dose wasreduced to a lower dose level stay on that dose level until the FinalVisit for the dose de-escalation phase. Three days after each doseup-titration or de-escalation, subjects are contacted by phone tomonitor study drug compliance, concomitant medication use, and adverseeffects. Any change in dose is documented in the subject's clinic chartand the subject's caregiver is advised to note the same in the dosingcard.

On Day 31, PK, PD, anti-epileptic drug, and PGx (if collected on Day 1)blood samples are collected before the morning dose of study drug andseizure data are also collected. On Day 41, PK, PD, and anti-epilepticdrug blood samples are collected before the morning dose of study drugand seizure data are also collected.

On Day 85, subjects return to the clinic for the Final Visit and enterthe 3- or 6-day de-escalation phase. At this visit, PK, PD, andanti-epileptic drug blood samples are collected before the morning doseof study drug and seizure data are also collected. Subjects then enterthe dose de-escalation phase and are instructed to follow the applicablede-escalation dosing schedule outlined below:

-   -   For subjects on 300 mg BID during the maintenance phase, the        dose is de-escalated to 200 mg BID for 3 days (Days 85-87) and        subsequently to 100 mg BID for 3 days (Days 88-90).    -   For subjects on 200 mg BID during the maintenance phase, the        dose is de-escalated to 100 mg BID for 3 days (Days 85-87).    -   For subjects on 100 mg BID during the maintenance phase, there        is no de-escalation and the dose is discontinued on Day 85.

Immediately after the last dose is the 30-day Follow-up Period comprisedof a Follow-up Phone Call on Day 91 and a Follow-up Visit on Day 121. Atthe Follow-up Visit, subjects return to the clinic for study proceduresincluding PD and AED blood sample collection.

In Parts 1 and 2, subjects are instructed to not take their morning doseof study drug or concomitant anti-epileptic drugs on the days ofscheduled study visits to facilitate collection of the predose PK, PD,anti-epileptic drug, and optional PGx blood samples. The morning dose ofstudy drug and concomitant anti-epileptic drug are administered in theclinic on these study days after laboratory samples are collected.

For subjects who are not able to come for the visit during the morninghours, they should be instructed to take their morning dose, as usual,and come to the study site during the afternoon hours, as feasible forthe subject. While in the clinic, the site should attempt to obtain 2 PKsamples, separated by 1-2 hours, if possible. Hours since the last doseof the study medication must be recorded in the eCRF upon collection ofthe PK sample(s).

Seizure data are recorded daily in the seizure diary by each subjectand/or subjects' caregiver throughout the Screening/Baseline Period upuntil the Follow-up Visit on Day 121 and is collected from the diary ateach visit.

Example 2 Pre-Clinical Seizure Model Data

The following Example provides data from a heterozygous deletion of aScnla mouse model (Scn1a+/− mice) of Dravet syndrome, a developmentalepileptic encephalopathy subtype. Myoclonic and generalized tonic-clonicseizures are observed, which correlate to symptoms in humans. Therefore,(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone wastested in Scn1a+/− mice for its potential effects on seizure. At 17-18days after birth, mice were weaned and started on treatment either withcontrol chow or chow containing (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone 0.02% (w/w) for 2 weeks. Spontaneousseizures were continuously monitored. The seizure free rate during thestudy period for the control group was 23.9%. In contrast, the seizurefree rate during the study period for the group treated with(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone was91.7%. These results support the use of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone totreat epileptic encephalopathies.

Example 3 Study in Pediatric Patients (Aged ≥2 and ≤17 Years) withDravet Syndrome and Lennox Gastaut Syndrome

This is a multicenter, randomized, double-blind, placebo-controlled,parallel-group, study in pediatric patients (aged ≥2 and ≤17 years) withDravet syndrome and Lennox Gastaut syndrome demonstrating ≥3 convulsiveor ≥4 drop seizures per month during the 3 months immediately prior toScreening (based on historic information) and ≥3 convulsive or ≥4 dropseizures during a minimum of 4 weeks during the prospective BaselinePeriod (based on the seizure diary records). Convulsive seizures includegeneralized tonic-clonic, focal to bilateral tonic-clonic with impairedawareness, hemi-clonic and simultaneous bilateral clonic (generalizedclonic) seizures. Drop seizures are defined as involving the entirebody, trunk, or head that leads to a fall, injury, slumping in a chair,or head hitting a surface, or that could have led to a fall or injury,depending on the position of the patient at the time of the seizure orspell. Examples of seizures causing drop include, but are not limitedto, atonic, clonic, and tonic seizures.

Approximately 126 patients will be randomized to ensure 112 evaluablepatients. Randomization will be stratified by 2 categories: patientswith Dravet syndrome with convulsive seizures and patients with LennoxGastaut Syndrome (LGS) with drop seizures. Stratification will beperformed to ensure balance of treatments within each stratum.

The study will begin with a phased enrollment based on age. Patientsaged ≥9 years will be enrolled first, prior to open enrollment in thestudy, for assessment of safety. The independent Data MonitoringCommittee (iDMC) will review the adverse event (AE) profile of the first20 patients aged ≥9 years completing treatment, prior to recommendingtreatment for patients aged <9 years.

This study consists of 2 main periods:

4- to 6-week Screening/Baseline Period

14-week Treatment Period

2-week Titration Period

12-week Maintenance Period

The Treatment Period consists of Titration Period and MaintenancePeriod.

Dravet syndrome patients who have had on average ≥3 convulsive or LGSpatients who have had on average ≥4 drop seizures per month during the 3months immediately prior to Screening (based on the historicalinformation) and ≥3 convulsive or ≥4 drop seizures during a minimum of 4weeks during the Baseline Period (based on the seizure diary records)will be eligible for entry into the study. The patients who meet theentry criteria will be randomized in a 1:1 ratio to double-blindtreatment with(4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone ormatching placebo for the 14-week Treatment Period (2-week TitrationPeriod and 12-week Maintenance Period).

Formulation Example

For (4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone,the formulation (film coating tablet) was produced in line with thefollowing specification (Table 2).

TABLE 2 Quantity per Tablet(mg) Components 20 mg Core Tablet(4-benzyl-4-hydroxypiperidin- 20 (Internal 1-yl)(2,4′-bipyridin-3-granules) yl)methanone Microcrystalline cellulose (PH101) 1.5Low-Substituted Hydroxypropyl 1.25 Cellulose (L-HPC 21) HydroxypropylCellulose 0.75 (External Low-Substituted Hydroxypropyl 1.25 granules)Cellulose (L-HPC 21) Magnesium Stearate 0.25 Coating (OPADRY Red03F45081) 0.508 Solution (OPADRY Yellow 03F42240) 0.508 Hypromellose2910¹⁾ (0.75) Polyethylene Glycol 8000¹⁾ (0.167) Titanium Dioxide¹⁾(0.083) Ferric Oxide, Red¹⁾ (0.008) Ferric Oxide, Yellow¹⁾ (0.008) Total26.016 ¹⁾These ingredients are components of OPADRY (registeredtrademark) Red 03F45081 and OPADRY (registered trademark) Yellow03F42240 (premixed coating materials).

INDUSTRIAL APPLICABILITY

According to the present invention, an efficient method of treating anepileptic encephalopathy in a mammal in need thereof, comprisingadministering a composition comprising an effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof to the mammal can be provided.

This application is based on patent application No. 62/553,070 filed onAug. 31, 2017 in the US, the contents of which are encompassed in fullherein.

1. A method of treating an epileptic encephalopathy in a mammal in needthereof, comprising administering a composition comprising an effectiveamount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof to the mammal.
 2. The method of claim 1, wherein the epilepticencephalopathy is selected from the group of Dravet syndrome, Earlymyoclonic encephalopathy, Epilepsy with continuous spike-and-wavesduring slow-wave sleep other than Landau-Kleffner syndrome, epilepsy ofinfancy with migrating focal seizures, Hypothalamic epilepsy,Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Doose syndrome,Myoclonic status in non-progressive encephalopathies, Ohtahara syndromeor early infantile epileptic encephalopathy, West syndrome, Glycineencephalopathy, 15q duplication syndrome and Tuberous Sclerosis Complexand seizures associated with mutations in CHD2, Cyclin-DependentKinase-Like 5, SCN1A, SCN2A, SCN8A, ARX, KCNA1, KCNA2, KCNT1, KCNQ2,HCN1, PCDH19, GRIN1, GRIN2A and GRIN2B.
 3. The method of claim 1,wherein the epileptic encephalopathy is selected from the group ofDravet syndrome, Lennox-Gastaut syndrome, Tuberous Sclerosis Complex andseizures associated with mutations in CHD2, Cyclin-Dependent Kinase-Like5, SCN1A, SCN2A, SCN8A, ARX, KCNA1, KCNA2, KCNT1, KCNQ2, HCN1, PCDH19,GRIN1, GRIN2A and GRIN2B.
 4. The method of claim 1, whereinadministering the effective amount of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof results in (i) a reduction in the frequency of seizures in themammal and/or (ii) a reduction in the plasma 24HC levels in the mammal.5. The method of claim 1, wherein the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered orally.
 6. Themethod of claim 1, wherein the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered as a singleunit dose.
 7. The method of claim 6, wherein the single unit dose is atleast about 0.8 mg/kg.
 8. The method of claim 6, wherein the single unitdose is between about 2 mg/kg and about 12 mg/kg.
 9. The method of claim6, wherein the single unit dose is selected from the consisting of about0.8 mg/kg, about 2 mg/kg, about 3 mg/kg, about 3.33 mg/kg, about 4mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, and about 12 mg/kg.10. The method of claim 1, wherein the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered according to adose regimen of either twice a day or once a day dosing.
 11. The methodof claim 1, wherein the mammal is a human.
 12. The method of claim 11,wherein the human is an adult, a juvenile, a child, or an infant. 13.The method of claim 11, wherein the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered as a singleunit dose.
 14. The method of claim 13, wherein the single unit dose isless than about 1350 mg.
 15. The method of claim 13, wherein the singleunit dose is between about 50 mg and about 800 mg.
 16. The method ofclaim 13, wherein the single unit dose is between about 100 mg and about800 mg.
 17. The method of claim 13, wherein the single unit dose isselected from the group consisting of about 100 mg, about 150 mg, about200 mg, about 300 mg, about 400 mg, about 600 mg and about 800 mg. 18.The method of claim 11, wherein the effective amount of(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof is administered twice a day.19. The method of claim 18, wherein (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone is administered at the daily dose ofbetween about 100 mg and about 800 mg.
 20. The method of claim 18,wherein (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone is administered according to a doseregimen selected from the group consisting of about 50 mg twice a day,about 100 mg twice a day, about 200 mg twice a day, about 300 mg twice aday and about 400 mg twice a day.
 21. The method of claim 18, wherein(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone isadministered according to a dose regimen of about 400 mg twice a day.22. The method of claim 1, further comprising administering anadditional composition comprising an effective amount of an additionalanti-epileptic drug.
 23. The method of claim 22, wherein the additionalanti-epileptic drug is selected from the group of acetazolamide,brivaracetam, bromide, cannabidiol, carbamazepine, clobazam, clonazepam,diazepam, eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoinsodium, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam,mephenytoin, methlyphenobarbital, methosuximide, nitrazepam,oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin,pregabalin, primidone, retigabine, rufinamide, sodium valproate,stiripentol, tiagabine, topiramate, fenfluramine, vigabatrin, andzonisamide.
 24. The method of claim 1, wherein the composition furthercomprises one or more of an additional anti-epileptic drug and apharmaceutically acceptable carrier.
 25. The method of claim 24, whereinthe additional anti-epileptic drug is selected from the group ofacetazolamide, brivaracetam, bromide, cannabidiol, carbamazepine,clobazam, clonazepam, diazepam, eslicarbazepine acetate, ethosuximide,felbamate, fosphenytoin sodium, gabapentin, lacosamide, lamotrigine,levetiracetam, lorazepam, mephenytoin, methlyphenobarbital,methosuximide, nitrazepam, oxcarbazepine, perampanel, piracetam,phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide,sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, andzonisamide.
 26. A pharmaceutical composition comprising(4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone or apharmaceutically acceptable salt thereof, which is for treating anepileptic encephalopathy.
 27. (4-Benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or a pharmaceutically acceptable saltthereof for use in treatment of epileptic encephalopathy.